In the search for the ideal, nonflammable, inhalational anesthetic a number of fluorinated compounds have been synthesized. Many have been associated with proven toxic reactions; all are potentially toxic. Halothane administration may lead to liver damage and occasional cases of fatal hepatic necrosis. Methoxyflurane causes dose-related polyuric, vasopressin-resistant nephrotoxicity in man and animals due primarily to its metabolism to inorganic fluoride. Enflurane and sevoflurane, although metabolized to inorganic fluoride to a lesser extent than methoxyflurane, still could cause renal damage. For example, patients with pre-existing renal disease may be at greater risk of developing fluoride nephrotoxicity when anesthetized with fluorinated anesthetics than patients with normal renal function. We will study the relationship of pre-existing renal impairment to the development of anesthetic nephrotoxicity in Fischer 344 rats, and animal model for inorganic fluoride nephropathy. Renal impairment will be produced surgically; anesthetic defluorination, renal function and morphology will be examined. Similarly, patients in whom anesthetic biotransformation is enhanced because of treatment with enzyme inducing agents may be more likely to develop fluoride nephrotoxicity or, perhaps, other adverse anesthetic-drug interactions. To identify agents which induce anesthetic metabolism we will carry out in vitro studies with rat hepatic microsomal preparations. Once identified, the effects of these inducing agents on the kinetics of anesthetic defluorination will be determined. Ordinary and deuterated anesthetics will be used so that we also may probe mechanisms of anesthetic biotransformation. The information gained from these in vitro and in vivo animal studies will enable us to more clearly define and solve the problems related to the renal effects and metabolism of fluorinated anesthetics in surgical patients.